Papers by Mohamed Rahmani
Interactions between the histone deacetylase (HDAC) inhibitors suberanoylanilide hydroxamic acid ... more Interactions between the histone deacetylase (HDAC) inhibitors suberanoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino 17-demethoxygeldanamycin (17-AAG) have been examined in Bcr-Abl ϩ human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571 (imatinib mesylate). Cotreatment with 17-AAG and SAHA or SB synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI571, as well as in CD34 ϩ cells isolated from the bone marrows of three patients with chronic myelogenous leukemia. These events were associated with increased binding of BcrAbl, Raf-1, and Akt to Hsp70, and inactivation of extracellular signal-regulated kinase 1/2 and Akt. In addition, 17-AAG/SAHA abrogated the DNA binding and the transcription...
Plants, 2021
Agriculture is facing many challenges, such as climate change, drought, and salinity, which call ... more Agriculture is facing many challenges, such as climate change, drought, and salinity, which call for urgent interventions for fast adaptation and crop diversification. The introduction of high-value and stress tolerant crops such as quinoa would be a judicious solution to overcome constraints related to abiotic stress and to increase land productivity and farmers’ incomes. The implementation of quinoa in Morocco has not been supported by a full valorization program to control the quality of quinoa seeds. The novelty of this work is to assess the pearling operation as an efficient method of saponins removal as well as the determination of total residual saponins. This study aimed to evaluate the effects of several pearling durations on nutrient and saponin content of quinoa seeds of three tested varieties (Puno, Titicaca, and ICBA-Q5). Five pearling durations were tested (0, 2, 4, 6, 7, and 8 min) using a locally manufactured pearling machine. The results indicated that a pearling du...
Cancer Research, 2006
4663 Recently, we reported that sequential administration of the benzamide HDAC inhibitor MS-275 ... more 4663 Recently, we reported that sequential administration of the benzamide HDAC inhibitor MS-275 and the nucleoside analog fludarabine (F) resulted in synergistic induction of apoptosis in human leukemia cells (Maggio et al, Cancer Res. 64, 2590; 2004). Herein, we extended this concept the hydroxamic acid HDAC inhibitor NVP-LAQ824, and investigated involvement of reactive oxygen species (ROS) as well as activation of the NF-kB and JNK pathways in mechanisms of lethality. Pre-exposure (24 h) of U937 cells to low, non-toxic concentrations (40nM) of NVP-LAQ824 followed by addition of F induced a dramatic increase in cell death (≥75%). Apoptosis correlated with activation of caspases 3, -7, -8 and -9, and mitochondrial injury (loss of mitochondrial membrane potential and cytoplasmic release of cytochrome c, AIF and Smac/DIABLO). No changes were detected in the levels of membrane-associated DR4 or DR5 death receptors. NVP-LAQ824 induced an early peak of ROS (30’-3h), which persisted for ...
Plants, 2021
Agricultural production in the Rehamna region, Morocco is limited with various challenges includi... more Agricultural production in the Rehamna region, Morocco is limited with various challenges including drought and salinity. Introduction of climate resilient and rustic crops such as quinoa was an optimal solution to increase farmer’s income and improve food security. This study summarizes results obtained from a research project aiming to develop quinoa value chain in Morocco. The study tackled several aspects including agronomic traits (yield and growth), transformation, quality (nutritional and antinutritional traits) and economic analysis and, finally, a strength–weaknesses–opportunities–threats analysis, lessons learned and development perspectives were presented. From an agronomic point of view, introduced new quinoa cultivars showed higher performance than locally cultivated seeds and, furthermore, the use of irrigation and organic amendment has tremendously improved seed yield by double and three times, respectively, compared to rainfed conditions. Nutritional analysis reveale...
Cancers, 2021
The major form of cell death in normal as well as malignant cells is apoptosis, which is a progra... more The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advance...
Blood, 2004
Ras mutations, which result in constitutive Ras activation, occur frequently in human malignancie... more Ras mutations, which result in constitutive Ras activation, occur frequently in human malignancies, including leukemia. This finding has prompted the development of farnesyltransferase inhibitors (FTIs), which interfere with Ras farnesylation and membrane translocation necessary for Ras function. However, FTIs alone have not yet fulfilled their clinical potential, raising the possibility that their role may lie in combination with other agents. The present studies examined interactions between the farnesyltransferase inhibitor L744832 and the Chk1 inhibitor UCN-01 in human leukemia cells. Combined exposure of U937 cells to sub-toxic concentrations of UCN-01 (100nM) and the FTI L744352 (10μM) resulted in a dramatic and highly synergistic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat) and primary AML blasts, and with other farnesyltransferase inhibitors (e.g., FTI-277). These ev...
Blood, 2004
Interactions between the histone deacetylase inhibitors (HDACIs) suberanoylanilide hydroxamic aci... more Interactions between the histone deacetylase inhibitors (HDACIs) suberanoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in Bcr-Abl+ human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571. Co-administration of 17-AAG with SAHA or SB for 24 h synergistically induced mitochondrial dysfunction (cytochrome c and AIF release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI-571 as well as in CD34+ leukemic cells obtained from patients with CML including those who had developed a resistance against STI-571. These events were associated with increased association of Bcr/abl, Raf-1, and Akt with Hsp70, whereas the total level of these proteins markedly decreased. A pronounced inactivation of ERK1/2, and activation of JNK were also observed. In addition, 17-AAG/SAHA abrogated DNA bi...
Haematologica, 2019
The pathogenesis of acute myeloid leukemia involves serial acquisition of mutations controlling s... more The pathogenesis of acute myeloid leukemia involves serial acquisition of mutations controlling several cellular processes, requiring combination therapies affecting key downstream survival nodes to effectively treat the disease. The BCL2 selective inhibitor venetoclax has potent antileukemia efficacy; however, resistance can occur due to its inability to inhibit MCL1, which is stabilized by the MAPK pathway. In this study, we aimed to determine the anti-leukemia efficacy of concomitant targeting of BCL2 and MAPK pathways by venetoclax and MEK1/2 inhibitor cobimetinib respectively. The combination demonstrated synergy in 7 of 11 acute myeloid leukemia cell lines, including those resistant to single agents, and showed growth-inhibitory activity in over 60% of primary patient samples with diverse genetic alterations. The combination markedly impaired leukemia progenitor functions, while maintaining normal progenitors. Mass cytometry data revealed that BCL2 protein is enriched in leukemia stem/progenitor cells, primarily in venetoclax-sensitive samples and that cobimetinib suppressed cytokine-induced pERK and pS6 signaling pathways. Through proteomic profiling studies, we identified several pathways inhibited downstream of MAPK that contribute to the synergy of the combination. In OCI-AML3 cells, the combination downregulated MCL1 protein levels and disrupted both BCL2:BIM and MCL1:BIM complexes, releasing BIM to induce cell death. RNA sequencing identified several enriched pathways, including MYC, mTORC1, and p53 in cells sensitive to the drug combination. In vivo, the venetoclax-cobimetinib combination reduced leukemia burden in xenograft models using genetically engineered OCI-AML3 and MOLM13 cells. Our data thus provide a rationale for combinatorial blockade of MEK and BCL2 pathways in acute myeloid leukemia. 4 Furthermore, predictive biomarkers of response to this combination in AML are unknown. Suppression of downstream pERK does not predict sensitivity to MEK inhibition. 21 In melanoma, it has been demonstrated that mTORC1/2 and pS6 activities are associated with acquired resistance to MEK inhibitors and suppression of pS6 may serve as a biomarker to predict clinical response to MEK inhibitors. 22, 23 The role of pS6 in response to MEK and BCL2 inhibition has not been addressed. In this study, we evaluated the anti-leukemia effects of concomitant BCL2 and MAPK blockade by venetoclax and cobimetinib in AML cell lines, primary patient samples, and xenograft murine models. Through the use of reverse-phase protein arrays (RPPA) and RNA sequencing, we identified pharmacodynamic markers that correlated with efficacy of the combination treatment, in particular activated pS6 (Ser235/236), which discriminated combination-sensitive frominsensitive AML cells. Our data support the rationale for dual inhibition of the BCL2 and MEK pathways. 5 Methods Patient samples, AML cell lines, and reagents Bone marrow and peripheral blood samples were collected from patients with AML or healthy donors after informed consent was obtained in accordance with the Institutional Review Board of The University of Texas MD Anderson Cancer Center. The cell line culture methodology is described in the Supplemental Methods. CellTiter-Glo proliferation assay Details are provided in the Supplemental Methods. Apoptosis in primary AML samples As previously reported, 24 18 primary AML peripheral blood mononuclear cells or AML PDX samples were cultured in LSC medium. Viable AML CD45 dim blast cells were enumerated by using CountBright counting beads (Cat. C36950; Invitrogen, Carlsbad, CA) with concurrent Annexin-V and DAPI detection on a Gallios Flow Cytometer (Beckman Coulter, Indianapolis, IN). Data analysis and additional details are included in Supplemental Methods. Colony-forming cell assay Details are provided in the Supplemental Methods. Electrochemiluminescent ELISA assay, reverse-phase protein array, and RNA sequencing Details are provided in the Supplemental Methods. Antibody conjugation for mass cytometry staining and the spanning-tree progression analysis of density-normalized events (SPADE) analysis Details are provided in the Supplemental Methods. In vivo study of cobimetinib and venetoclax in AML xenograft mouse models The animal studies were performed in accordance with guidelines approved by the Institutional Animal Care and Use Committee at MD Anderson. Nonobese diabetic/severe combined immunodeficient gamma IL3-GM-SF (NSG-SGM3 or NSGS) mice (female, 8-10 weeks old) were purchased from Jackson Laboratory (Bar Harbor, ME). The mice were injected
HortScience, 2005
Morocco is the world's leading caper producer. Its export position has declined as worldwide ... more Morocco is the world's leading caper producer. Its export position has declined as worldwide production increases. Farm gate prices have declined as market prices have diminished. A joint program among the Moroccan Federation of Food Processors (FICOPAM), the Institut Agronomique et Veterinaire Hassan II (IAV Hassan II), and DAI was supported by USAID to examine how to improve industry competitiveness. Field surveys and workshops with farmers, buyers, and processors in Morocco's three main caper growing regions were used to inform a national conference to arrive at a consensus action plan. The plan focuses on a shift from weight-based to grade-based buying practices. Supporting changes were identified to modify on-farm practice; equip and regulate buying floors at major markets; institute minimum traceability requirements; and establish HACCP programs for caper processors in collaboration with Moroccan export authorities. Training programs to support these changes were compl...
Molecular Pharmacology, 2002
Previous studies have shown that coexposure to marginally toxic concentrations of phorbol 12-myri... more Previous studies have shown that coexposure to marginally toxic concentrations of phorbol 12-myristate 13-acetate (PMA; 10 nM) and the cyclin-dependent kinase inhibitor flavopiridol (FP; 100-200 nM) synergistically induces apoptosis in human myeloid leukemia cells U937 and HL-60 (i.e., Ͼ50% apoptotic at 24 h). Attempts have now been made to characterize the cell death pathway(s) involved in this phenomenon. In contrast to cytochrome c release and caspase-3 activation, which occur within 2.5 h of PMA/FP coexposure, caspase-8 activation and Bid cleavage appeared as later events. Such findings implicate the mitochondria-dependent pathway in the initial induction of apoptosis by PMA/FP. However, U937 cells ectopically expressing CrmA, dominant-negative caspase-8, or dominantnegative Fas-associated death domain that were highly resistant to tumor necrosis factor (TNF)/cycloheximide-induced lethality displayed significant, albeit incomplete, resistance to PMA/FP-induced apoptosis after 24 h. Furthermore, coadministration of TNF soluble receptor significantly attenuated PMA/ FP-induced apoptosis in U937 (p Ͻ 0.02) and HL-60 (p Ͻ 0.03) cells at 24 h. PMA/FP coadministration also triggered substantial increases in TNF␣ mRNA and protein secretion compared with the effects of PMA administered alone. The protein kinase C (PKC) inhibitor bisindolylmaleimide (1 M) completely blocked PMA/FP-induced TNF␣ secretion in U937 cells and attenuated apoptosis. Taken together, these results suggest that coadministration of PMA with FP in myeloid leukemia cells initially triggers mitochondrial damage, an event followed by the PKC-dependent induction and release of TNF␣, supporting a model in which the synergistic induction of leukemic cell apoptosis by this drug combination proceeds via both mitochondrial-and TNF receptor-related apoptotic pathways. Apoptosis was originally described as a series of morphological changes exhibited by dying cells in biological systems (Kerr et al., 1972). It is a highly conserved process of cell suicide that involves the activation of a family of cysteine proteases known as caspases (Earnshaw et al., 1999). Caspases are the primary executioners of apoptosis, and their activation is responsible for the characteristic biochem
Blood, Jan 11, 2015
Chromodomain Helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleo... more Chromodomain Helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double stranded break (DSB) repair. Here, we show that depletion of CHD4 in Acute Myeloid Leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the ATM pathway, which is preliminarily activated by a Tip60-dependent mechanism in response to chromatin relaxation and further activated by genotoxic-agent induced DSBs. This sensitization preferentially affects AML cells, as CHD4 depletion in normal CD34(+) hematopoetic progenitors does not increase their susceptibility to DNR or ara-C. Unexpectedl...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2014
The aim of this study is to explore the efficacy and define mechanisms of action of coadministrat... more The aim of this study is to explore the efficacy and define mechanisms of action of coadministration of the PI3K/mTOR inhibitor BEZ235 and pan-HDAC inhibitor panobinostat in diffuse large B-cell lymphoma (DLBCL) cells. Various DLBCL cells were exposed to panobinostat and BEZ235 alone or together after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Genetic strategies defined the functional significance of such changes, and xenograft mouse models were used to assess tumor growth and animal survival. Panobinostat and BEZ235 interacted synergistically in ABC-, GC-, and double-hit DLBCL cells and MCL cells but not in normal CD34(+) cells. Synergism was associated with pronounced AKT dephosphorylation, GSK3 dephosphorylation/activation, Mcl-1 downregulation, Bim upregulation, increased Bcl-2/Bcl-xL binding, diminished Bax/Bak binding to Bcl-2/Bcl-xL/Mcl-1, increased γH2A.X phosphorylation and histone H3/H4 acetylati...
Computer and Information Science, 2010
In this article we present a 2D cellular automaton (Class_AC) to solve a problem of text mining i... more In this article we present a 2D cellular automaton (Class_AC) to solve a problem of text mining in the case of unsupervised classification (clustering). Before to experiment the cellular automaton, we vectorized our data indexing textual documents from the database REUTERS 21,578 by Wordnet approach and the representation of text documents by the method n-grams. Our work is to make a comparative study of two approaches to representation that is the conceptual approach (Wordnet) and the n-grams. Section 1 gives an introduction on the biomimétisme and text mining, Section 2 presents representation of texts based on Wordnet approach and the n grams, Section 3 describes the cellular automaton for clustering, Section 4 shows the experimentation and comparison results and finally Section 5 gives a conclusion and perspectives.
International Journal of Regulation and Governance, 2012
Given the limited performance of 2D cellular automata in terms of space when the number of docume... more Given the limited performance of 2D cellular automata in terms of space when the number of documents increases and in terms of visualization clusters, our motivation was to experiment these cellular automata by increasing the size to view the impact of size on quality of results. The representation of textual data was carried out by a vector model whose components are derived from the overall balancing of the used corpus Term Frequency-Inverse Document Frequency (TF-IDF).The WorldNet thesaurus has been used to address the problem of the lemmatization of the words because the representation used in this study is that of the bags of words. Another independent method of the language was used to represent textual records is that of the n-grams. Several measures of similarity have been tested. To validate the classification we have used two measures of assessment based on the recall and precision (f-measure and entropy). The results are promising and confirm the idea to increase the dimension to the problem of the spatiality of the classes. The results obtained in terms of purity class (ie the minimum value of entropy) shows that the number of documents over longer believes the results are better for 3D cellular automata, which was not obvious to 2D the dimension. In terms of spatial navigation, cellular automata provide very good 3D performance visualization than 2D cellular automata.
PLoS ONE, 2014
Staphylococcus pseudintermedius is a major cause of skin and soft tissue infections in companion ... more Staphylococcus pseudintermedius is a major cause of skin and soft tissue infections in companion animals and has zoonotic potential. Additionally, methicillin-resistant S. pseudintermedius (MRSP) has emerged with resistance to virtually all classes of antimicrobials. Thus, novel treatment options with new modes of action are required. Here, we investigated the antimicrobial activity of six synthetic short peptides against clinical isolates of methicillin-susceptible and MRSP isolated from infected dogs. All six peptides demonstrated potent antistaphylococcal activity regardless of existing resistance phenotype. The most effective peptides were RRIKA (with modified C terminus to increase amphipathicity and hydrophobicity) and WR-12 (a-helical peptide consisting exclusively of arginine and tryptophan) with minimum inhibitory concentration 50 (MIC 50) of 1 mM and MIC 90 of 2 mM. RR (short anti-inflammatory peptide) and IK8 ''D isoform'' demonstrated good antimicrobial activity with MIC 50 of 4 mM and MIC 90 of 8 mM. Penetratin and (KFF) 3 K (two cell penetrating peptides) were the least effective with MIC 50 of 8 mM and MIC 90 of 16 mM. Killing kinetics revealed a major advantage of peptides over conventional antibiotics, demonstrating potent bactericidal activity within minutes. Studies with propidium iodide and transmission electron microscopy revealed that peptides damaged the bacterial membrane leading to leakage of cytoplasmic contents and consequently, cell death. A potent synergistic increase in the antibacterial effect of the cell penetrating peptide (KFF) 3 K was noticed when combined with other peptides and with antibiotics. In addition, all peptides displayed synergistic interactions when combined together. Furthermore, peptides demonstrated good therapeutic indices with minimal toxicity toward mammalian
The human T cell repertoire is complex and is generated by the rearrangement of variable (V), div... more The human T cell repertoire is complex and is generated by the rearrangement of variable (V), diversity (D) and joining (J) segments on the T cell receptor (TCR) loci. The T cell repertoire demonstrates self-similarity in terms clonal frequencies when defined by V, D and J gene segment usage; therefore to determine whether the structural ordering of these gene segments on the TCR loci contributes to the observed clonal frequencies, the TCR loci were examined for self-similarity and periodicity in terms of gene segment organization. Logarithmic transformation of numeric sequence order demonstrated that the V and J gene segments for both T cell receptor α (TRA) and β (TRB) loci were arranged in a self-similar manner when the spacing between the adjacent segments was considered as a function of the size of the neighboring gene segment, with an average fractal dimension of ~1.5. The ratio of genomic distance between either the J (in TRA) or D (in TRB) segments and successive V segments ...
Pharmacology & Therapeutics, 2010
The cytokine melanoma differentiation associated gene 7 (mda-7) was identified by subtractive hyb... more The cytokine melanoma differentiation associated gene 7 (mda-7) was identified by subtractive hybridization as a protein whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared to nontransformed cells. Based on conserved structure, chromosomal location and cytokine-like properties, MDA-7, was classified as a member of the interleukin (IL)-10 gene family and designated as MDA-7/ IL-24. Multiple studies have demonstrated that expression of MDA-7/IL-24 in a wide variety of tumor cell types, but not in corresponding equivalent non-transformed cells, causes their growth arrest and rapid cell death. In addition, MDA-7/IL-24 has been noted to radiosensitize tumor cells which in part is due to the generation of reactive oxygen species (ROS) and ceramide that cause endoplasmic reticulum stress and suppress protein translation. Phase I clinical trial data has shown that a recombinant adenovirus expressing MDA-7/IL-24 (Ad.mda-7 (INGN-241)) was safe and had measurable tumoricidal effects in over 40% of patients, strongly arguing that MDA-7/IL-24 could have significant therapeutic value. This review describes what is presently known about the impact of MDA-7/IL-24 on tumor cell biology and its potential therapeutic applications.
Molecular Cancer Therapeutics, 2009
Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displ... more Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on clarifying the mechanism(s) by which glutathione S-transferase (GST)-MDA-7 altered cell survival of human renal carcinoma cells in vitro. GST-MDA-7 caused plasma membrane clustering of CD95 and the association of CD95 with procaspase-8. GST-MDA-7 lethality was suppressed by inhibition of caspase-8 or by overexpression of short-form cellular FLICE inhibitory protein, but only weakly by inhibition of cathepsin proteases. GST-MDA-7–induced CD95 clustering (and apoptosis) was blocked by knockdown of acidic sphingomyelinase or, to a greater extent, ceramide synthase-6 expression. GST-MDA-7 killing was, in parallel, dependent on inactivation of extracellular signal–regulated kinase 1/2 and on CD95-induced p38 mitogen-activated protein kinase and c-jun NH2-terminal kinas...
Molecular Cancer Therapeutics, 2008
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displ... more Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R–like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK−/− cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B–dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) express...
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Papers by Mohamed Rahmani